Joint Mechanical Engineering and Biomedical Engineering Seminar: Dr. Jong-Hoon Nam

The actions of calcium on the mechano-transduction of mammalian cochlear hair cells

Department of Physiology, University of Wisconsin-Madison

Abstract

Hair cells are the sensory receptors of the inner ear where mechanical stimuli of sound, vibration or gravity turn into electric signals. In the cochlea, the vibration of membranes is detected by rocking of the hair cell stereociliary bundles (HCB), which leads to opening of mechano-transduction channels. The transducer channel is highly permeable to calcium, which plays a crucial role for sensitivity and adaptation of the hair cells. This presentation comprises three parts which combine experiments and simulations to understand the effect of Ca²⁺ on the HCB mechanics and mechano-transduction.

First, the mechanical properties of the HCB: By delivering force stimuli with a calibrated flexible fiber, we measured HCB mechanics and transduction currents in isolated rat cochleas. The HCB mechanics were nonlinear and influenced by various conditions affecting intracellular Ca²⁺ concentration. To analyze these results, we developed a finite element model of a rat cochlear HCB. Bundle geometric properties were obtained from electron micrographs. The mechanical properties of the bundle structural components were identified by matching experiment results with equivalent simulations. Second, theoretical conditions for hair cell spontaneous oscillations: We introduced a ten-state channel kinetics model which is determined by the channel configuration and the number of bound calcium. The channels were stochastically gated and their open probability was determined by the tension applied to the channel and by the calcium binding states.

The results suggest that the channel-HCB interaction regulated by Ca²⁺ can select and amplify faint sound signals. Third, the location of transducer channels in the HCB: Although evidence suggests that the transducer channels are near the stereociliary tips, the exact location has been controversial. To localize the channels we used fast confocal imaging of calcium fluorescence in the HCB during stimulation. A computational model of Ca²⁺ diffusion dynamics was developed which incorporates Ca²⁺ influx through transduction channels, binding to mobile and fixed buffers uptake into mitochondria and extrusion by CaATPase pumps. The calcium fluorescence images supported by theoretic simulations imply that the mechano-transduction channels are at the lower end of the tip links.